Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-].CO>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][O:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH3:16]
Reactant: OCC1CCCCO1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)COCC1CCCCO1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.1 %

Procedure:
To a solution of tetrahydropyran-2-methanol (1.13 mL, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (11 mg) followed by ethyl diazoacetate (1.05 mL, 10.0 mmol). The reaction mixture is stirred at rt for 20 min. To the reaction mixture is added MeOH (0.5 mL), and the solvents rotary evaporated. The residue is purified by chromatography on silica gel; elution with EtOAc:heptane (30:70) gives 1.66 g of the product 458. 1H NMR (CDCl3) δ 4.3-4.1 (m, 4H), 4.0 (m, 1H), 3.6-3.4 (m, 4H), 1.85 (m, 1H), 1.6-1.3 (m, 5H), 1.25 (t, 3H); MS: m/z 203 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH:24]=[CH2:25])(=[O:23])=[O:22])=[CH:16][CH:15]=2)[N:10]=[CH:9][C:8]=1[CH2:26][C:27]([NH2:29])=[O:28]>CO.C(NCC)C>[CH2:5]([N:6]([CH2:7][CH3:8])[CH2:25][CH2:24][S:21]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:11]2[N:10]=[CH:9][C:8]([CH2:26][C:27]([NH2:29])=[O:28])=[C:7]([NH:6][CH2:5][C:4]3[CH:30]=[C:31]([F:33])[CH:32]=[C:2]([F:1])[CH:3]=3)[CH:12]=2)=[CH:19][CH:18]=1)(=[O:23])=[O:22])[CH3:4]
Reactant: C=CS(=O)(=O)Nc1ccc(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)cc1
Solvent: CCNCC
Solvent: CO
Product: CCN(CC)CCS(=O)(=O)Nc1ccc(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)cc1
Yield: 29 %

Procedure:
89 mg of 4-[(3,5-difluorobenzyl)amino]-6-({4-[(vinylsulfonyl)amino]phenyl}amino)pyridine-3-carboxyamide (the compound of Example 303) was dissolved in 1 mL of methanol, to which 0.28 mL of diethylamine was added, and stirred using a microwave reaction apparatus in an argon atmosphere at 120° C. for 30 minutes. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:ammonia methanol=10:1), and solidified in acetone-ether to obtain 41 mg (yield 29%: 2 steps) of the title compound as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]=[CH2:12])=[C:9]([NH2:13])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[C:18]([F:31])[C:17]=1[F:32].[F-].[Cs+]>COCCOC.O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]=[CH2:12])=[C:9]([NH2:13])[N:8]=[C:7]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[C:17]([F:32])[C:18]=2[F:31])[N:6]=1)=[O:4]
Reactant: CC1(C)OB(c2ccc(Cl)c(F)c2F)OC1(C)C
Reactant: C=Cc1c(N)nc(Cl)nc1C(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: C=Cc1c(N)nc(-c2ccc(Cl)c(F)c2F)nc1C(=O)OC
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 36.7 %

Procedure:
6-Amino-2-chloro-5-vinylpyrimidine-4-carboxylic acid methyl ester (0.6 g, 2.81 mmol), 2-(4-chloro-2,3-difluorophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.0 g, 3.65 mmol), bis(triphenylphosphine)-palladium(II) dichloride (197 mg, 0.28 mmol), and cesium fluoride (0.85 g, 5.6 mmol) were combined in 10 mL of 1,2-dimethoxyethane (DME) and 10 mL of water. The reaction mixture was heated in a CEM microwave reactor at 100° C. for 15 min (other temperature/time pairs used in the subsequent examples were 110° C. for 15 min; 150° C. for 5 min). The cooled reaction mixture was diluted with ethyl acetate, washed with water, dried and concentrated. The product was purified by flash chromatography on silica gel (ethyl acetate/hexane gradient) to yield the title compound (0.336 g, 36.7% yield) as a yellow solid (mp 130-132° C.); 1H NMR (CDCl3) δ 7.74 (m, 1H), 7.22 (m, 1H), 6.8 (dd, 1H), 5.62-5.7 (m, 2H), 5.67 (m, 1H), 5.42 (br s, 2H), 3.94 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25](O)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:28][C@@H:29]1[CH2:34][CH2:33][C@@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C@@H:31]([F:43])[CH2:30]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:28][C@H:29]4[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])[C@H:31]([F:43])[CH2:30]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](N)C[C@@H]1F
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)[C@H](F)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and tert-butyl [(1R*,2S*,4R*)-4-amino-2-fluorocyclohexyl]carbamate (example C55) the title compound is obtained as pale yellow foam.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)=[O:5].C(=O)([O-])[O-].[K+].[K+].[Br:26][CH2:27][CH2:28][CH2:29][CH2:30]Br>CC(C)=O>[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][O:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)=[O:5]
Reactant: BrCCCCBr
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCCCCBr

Procedure:
A suspension of 7.5 g of 2-hydroxy-N-(1H-indol-4-yl)benzamide and 8.28 g of potassium carbonate in 150 ml of acetone was refluxed for 75 minutes with 18 ml of 1,4-dibromobutane and the mixture was cooled. The precipitate was filtered off and rinsed with acetone and the filtrate was evaporated to dryness. The residue was purified by chromatography over silica (eluant:methylene chloride/ethyl acetate 9:1), followed by crystallization from ethyl acetate to obtain 2-(4-bromobutoxy)-N-(1H-indol-4-yl)benzamide melting at 135° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.C(N(CC)CC)C.[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[S:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=2[CH:14]=1)(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: CC1(C)OC(=O)Nc2ccc(N)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OC(=O)Nc2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)cc21
Reaction time: 0.17 h
Yield: 8.3 %

Procedure:
To a stirred solution of 6-amino-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (0.05 g, 0.24 mmol) in methylene chloride (2 mL) at 0° C. was added triethylamine (0.05 mL, 0.36 mmol). After 10 minutes, 2,3-dichlorobenzenesulfonyl chloride (0.06 g, 0.24 mmol) was added. The solution was stirred for 2 hours, then partitioned between ammonium chloride solution (sat.) and methylene chloride. The organic layer was dried over magnesium sulfate and concentrated. Flash silica gel column separation with 50% ethyl acetate/hexane followed by trituration with ether gave 2,3-dichloro-N-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)benzenesulfonamide as a white solid (0.008 g, 8%). 1H NMR (DMSO-d6): δ 10.57 (s, 1H), 10.16 (s, 1H), 7.97 (dd, J=7.9, 1.3 Hz, 1H), 7.92 (dd, J=8.0, 1.3 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 6.93 (m, 2H), 6.74 (d, J=8.4 Hz, 1H), 1.46 (s, 6H). MS (ESI) m/z 401/403/405 ([M+H]+); MS (ESI) m/z 399/401/403 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=1[O:25][CH:26]([CH2:29][F:30])[CH2:27][F:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(C)C>O>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([NH:16][C:12]2[C:7]3[C:6]([CH3:15])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[S:14][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:18]([O:25][CH:26]([CH2:27][F:28])[CH2:29][F:30])[CH:19]=1)#[N:22]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: N#Cc1ccc(N)c(OC(CF)CF)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1sc2ncnc(Nc3ccc(C#N)cc3OC(CF)CF)c2c1C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (0.2 g), 4-amino-3-(2-fluoro-1-fluoromethyl-ethoxy)-benzonitrile (0.17 g), p-toluenesulfonic acid monohydrate (0.16 g) and isopropanol (3.0 ml) were stirred at 90° C. for 2 hours. Then the mixture was poured in water and filtrated. The solid was washed with water and dried in an oven at 70° C.
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[C:11]([C@@H:16]2[CH2:18][C@H:17]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:13][C:14]=1[F:15])C1C=CC=CC=1.[H][H]>C(O)C.C1COCC1.[Pd]>[NH2:8][C:9]1[CH:10]=[C:11]([C@@H:16]2[CH2:18][C@H:17]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: [H][H]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(F)c(NCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(F)c(N)c1

Procedure:
262 mg (purity 66%, 0.55 mmol) of (+/−)-ethyl 2-[3-(benzylamino)-4-fluorophenyl]-trans-cyclopropanecarboxylate were dissolved in 5 ml of ethanol/THF (1:1), 26 mg of palladium on carbon (10%) were added and the mixture was hydrogenated at RT using a hydrogen pressure of 1 bar for 24 h. The reaction mixture was then filtered through celite, the residue was washed with ethanol and the filtrate was concentrated. The crude product obtained in this manner was purified by preparative HPLC. This gave 87 mg (69% of theory) of the target compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10](=O)[CH3:11].[NH2:13][NH2:14].C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1>[CH3:9][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]2[C:3]=1[C:10]([CH3:11])=[N:13][NH:14]2
Reactant: COc1cccc(F)c1C(C)=O
Reactant: NN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cccc2[nH]nc(C)c12
Temperature: 135 °C

Procedure:
A solution of 1-(2-fluoro-6-methoxyphenyl)ethanone (1 g), hydrazine (1.04 g), and sodium acetate (0.49 g) was stirred for 72 hours in toluene (10 mL). The mixture was concentrated, taken up in DMSO (8 mL), and heated to 135° C. for 24 hours. The mixture was cooled, poured into ethyl acetate (200 mL), and rinsed with 3× water, and brine. The organic layer was concentrated and chromatographed on silica gel using 10-100% ethyl acetate/hexanes.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]2[C:5]([CH:6]=[C:7]([C:16]3[S:17][CH:18]([CH2:21][C:22]([OH:24])=O)[CH2:19][N:20]=3)[NH:8]2)=[CH:4][C:3]=1[O:25][C:26]1[CH:27]=[N:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=1.O[N:37]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N>CN(C)C=O>[F:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]2[C:5]([CH:6]=[C:7]([C:16]3[S:17][CH:18]([CH2:21][C:22]([NH2:37])=[O:24])[CH2:19][N:20]=3)[NH:8]2)=[CH:4][C:3]=1[O:25][C:26]1[CH:27]=[N:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=1
Reactant: On1nnc2ccccc21
Reactant: COCCOc1c(F)c(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: COCCOc1c(F)c(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 0 °C
Yield: 62.3 %

Procedure:
To an ice-cooled and stirred mixture of {2-[6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (135 mg) in N,N-dimethylformamide (7 mL) were added 1-hydroxybenzotriazole (70 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg). After stirring at 4° C. to room temperature for 15 h, the reaction mixture was cooled on an ice bath and 10% aqueous ammonia solution (1.0 mL) was added thereto. The mixture was stirred at room temperature for 5 h and partitioned between ethyl acetate and water. The organic layer was washed with aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated to give light yellow crystals, which were recrystallized from tetrahydrofuran-ethyl acetate to give the title compound (84 mg) as pale yellow crystals. MS 523 (MH+). mp 143-144° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].C(N(CC)CC)C.F[C:15]1[C:22]([F:23])=[CH:21][CH:20]=[C:19]([O:24][CH3:25])[C:16]=1[CH:17]=O>CN(C)C=O>[F:23][C:22]1[C:15]2[S:3][C:2]([C:1]([O:5][CH3:6])=[O:4])=[CH:17][C:16]=2[C:19]([O:24][CH3:25])=[CH:20][CH:21]=1
Reactant: COC(=O)CS
Reactant: COc1ccc(F)c(F)c1C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(OC)ccc(F)c2s1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 87.4 %

Procedure:
Methyl thioglycolate (28.8 mL, 320 mmol) was added under nitrogen to a solution of triethylamine (86.6 mL) in dry NN-dimethylformamide (220 mL) at 80° C. Stirred at 100° C. for 15 mins. A solution of 2,3-difluoro-6-methoxybenzaldehyde (55.1 g, 320 mmol) in N,N-dimethylformamide (80mL) was added and the mixture heated at 130° C. for 3h. Allowed to cool then poured onto ice-water (2L). The resulting yellow solid was filtered, washing with water (2×200 mL). Dried under vacuum over phosphorus pentoxide at room temperature overnight to give the title compound (67.2 g, 87%); δH (300 MHz, CDCl3) 8.20 (1H, d, ArH), 7.06 (1H, t, ArH), 6.68 (1H, m, ArH) and 3.99 (6H, s, OCH3 and CO2CH3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=O)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:12][O:13][C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl.O>[CH3:12][O:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[CH2:15]1
Reactant: CO[C@H]1CCNC1
Reactant: O=Cc1ccc([N+](=O)[O-])cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CO[C@H]1CCN(Cc2ccc([N+](=O)[O-])cn2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a stirred solution of 31 (0.4 g, 2.6 mmol) and (S)-3-methoxy-pyrrolidine (0.4 g, 3.2 mmol) in dichloromethane (10 mL) was added acetic acid (0.01 mL, 0.25 mmol). After 30 minutes, sodium triacetoxyborohydride (1.1 g, 5.3 mmol) was added to the above mixture and stirred at rt for 15 minutes. The reaction mixture was diluted with water (10 mL), treated with saturated NaHCO3 solution to get pH˜8 and extracted with dichloromethane (2×20 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4) and evaporated. The crude compound was purified by silica gel flash chromatography, eluting with 2% MeOH/DCM to afford 32 (0.25 g, 40%) as a liquid. Rf: 0.3 (5% MeOH/DCM); (m/z): 238 [MH]+; 1H NMR (400 MHz, DMSO-d6): δ 9.28 (1H, d, J=2.8 Hz), 8.59-8.56 (1H, m), 7.71 (1H, d, J=8.8 Hz), 3.93-3.80 (3H, m), 3.16 (3H, s), 2.73-2.62 (2H, m), 2.56-2.53 (1H, m), 2.50-2.47 (1H, m), 2.06-2.02 (1H, m), 1.72-1.65 (1H, m).
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:23]([C:25]3[N:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)=[CH:27][N:26]=3)=S)[CH2:19][CH2:18]1)(=[O:16])=[O:15])=[CH:8]2.O.[NH2:38][NH2:39]>[Hg](Cl)Cl.C(Cl)Cl>[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[N:38][NH2:39])[C:25]3[N:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)=[CH:27][N:26]=3)[CH2:19][CH2:18]1)(=[O:16])=[O:15])=[CH:8]2
Reactant: NN
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCN(C(=S)c2ncc(-c3ccncc3)cn2)CC1
Agent: Cl[Hg]Cl
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: NN=C(c1ncc(-c2ccncc2)cn1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 6899.4 %

Procedure:
In a mixed solvent of ethanol (100 ml) and methylene chloride (100 ml) was suspended 1-[(5-chloroindol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]thiocarbonyl]piperazine (499 mg) at room temperature, followed by the successive addition of hydrazine monohydrate (146 μg) and mercury (II) chloride (272 mg). The resulting mixture was stirred at room temperature for 4 hours. After the solvent was distilled off, the residue was purified by chromatography on a silica gel column (8% methanol—methylene chloride). Methylene chloride was added and the resulting mixture was concentrated. Yellow crystals thus precipitated were collected by filtration and dried, whereby the title compound (100 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:20]1[N:25]=[C:24]([CH:26]=O)[CH:23]=[CH:22][CH:21]=1.[CH3:28][C:29]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[C:30]=1[NH2:31]>C(O)C>[C:29]1([CH3:28])[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[C:30]=1[N:31]=[CH:26][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[CH2:9][NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:25]=1
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: Cc1ccccc1NCc1ccc2ccccc2c1-c1cccc(C=O)n1
Solvent: CCO
Product: Cc1cc(C)c(N=Cc2cccc(-c3c(CNc4ccccc4C)ccc4ccccc34)n2)c(C)c1

Procedure:
A mixture of 1.50 g (4.26 mmol) of 6-(2-{[(2-methylphenyl)amino]methyl}-1-naphthyl)pyridine-2-carbaldehyde and 0.58 g (4.26 mmol) 2,4,6-trimethylaniline in 15 ml of dry ethanol was refluxed for 3 h. The resulting mixture was evaporated to dryness. The product was isolated from the residue by flash chromatography on silica gel 60 (40-63 um; eluent: hexanes-ethyl acetate=5:1, vol.). Yield 1.80 g (90%) of yellow oil. Anal. calc. for C33H31N3: C, 84.40; H, 6.65; N, 8.95. Found: C, 84.62; H, 6.73; N, 8.88. 1H NMR (CDCl3): 8.37 (m, 1H, 3-H in Py), 8.36 (s, 1H, CH═N), 7.97 (m, 1H, 4-H in Py), 7.93 (d, J=8.3 Hz, 1H, 4-H in naphthyl), 7.90 (m, 1H, 8-H in naphthyl), 7.68 (d, J=8.3 Hz, 1H, 3-H in naphthyl), 7.66 (m, 1H, 5-H in Py), 7.49 (m, 1H, 7-H in naphthyl), 7.39-7.44 (5,6-H in naphthyl), 7.03 (m, 1H, 5-H in Ph), 7.01 (m, 1H, 3-H in ortho-tolyl), 6.89 (s, 2H, 3,5-H in mesityl), 6.62 (m, 1H, 4-H in ortho-tolyl), 6.65 (m, 1H, 6-H in ortho-tolyl), 4.27 (m, 2H, CH2N), 3.97 (br. s, 1H, NH), 2.29 (s, 3H, Me in ortho-tolyl), 2.14 (s, 6H, 2,6-Me in mesityl), 2.08 (s, 3H, 4-Me in mesityl).
Reaction SMILES: N12CCN(CC1)CC2.[OH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[CH:20]=O)=[N:17][C:16]([O:22][CH3:23])=[CH:15][CH:14]=2.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:36][O:37][C:38](=[O:41])[CH:39]=[CH2:40]>C(OCC)(=O)C>[CH3:36][O:37][C:38]([C:39]1[CH2:40][O:9][C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[CH:20]=1)=[N:17][C:16]([O:22][CH3:23])=[CH:15][CH:14]=3)=[O:41]
Reactant: COc1ccc2ncc(O)c(C=O)c2n1
Reactant: C=CC(=O)OC
Agent: C1CN2CCN1CC2
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C1=Cc2c(cnc3ccc(OC)nc23)OC1
Temperature: 25 °C
Yield: 53 %

Procedure:
1,4-Diazabicyclo[2.2.2]octane (522 mg, 4.65 mmol, 1.0 eq) is added at room temperature to a stirred suspension of 3-hydroxy-6-methoxy-[1,5]naphthyridine-4-carbaldehyde (950 mg, 4.65 mmol, 1.0 eq) in acrylic acid methyl ester (20 mL) and the resulting mixture is heated under reflux for 3 hours. The reaction mixture is then cooled down to room temperature, solvent is removed and the residue is dissolved in 1,2-dichloroethane (20 mL). Triethylamine (19.5 mL, 139.6 mmol, 30.0 eq) is then added at 0° C., followed by methanesulfonyl chloride (3.85 mL, 69.8 mml, 15.0 eq) and the resulting mixture is heated under reflux for 4 hours. Solvent is removed and the residue is extracted with dichloromethane (3×40 mL) and water (40 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 10:1 to 5:1, v/v) to afford 6-methoxy-2H-1-oxa-5,9-diaza-phenanthrene-3-carboxylic acid methyl ester as a light yellow oil (670 mg, 53% yield).
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.C(N(CC)CC)C.Cl[C:19]1[N:24]=[C:23]([Cl:25])[CH:22]=[C:21]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:28]=2[CH3:34])[N:20]=1>COCCOC.O>[Cl:25][C:23]1[CH:22]=[C:21]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:28]=2[CH3:34])[N:20]=[C:19]([NH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:24]=1
Reactant: CCOC(=O)CN
Reactant: Cc1cccc(Nc2cc(Cl)nc(Cl)n2)c1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CNc1nc(Cl)cc(Nc2cccc(C)c2C)n1

Procedure:
A suspensione of 100% sodium hydride (27 mg) in anhydrous 1,2-dimethoxyethane (1.5 ml) is treated with small amounts of NH2CH2CO2C2H5.HCl (156 mg). Triethylamine (0.16 ml) and 2,4-dichloro-6-(2,3-xylidino)-pyrimidine (300 mg) are added, and the mixture is refluxed for 18 hours. Triethylamine (0.16 ml) is added again, heating under reflux for 24 hours more. Finally, after cooling, the reaction mixture is diluted with water and extracted with methylene chloride. The organic phase is washed to neutrality and dried over Na2SO4. By evaporation of the solvent and crystallization from ethyl acetate 300 mg of ethyl ester of N-[4-chloro-6-(2,3xylidino)-2-pyrimidinyl]-aminoacetic acid (I, 2) are obtained.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:17][N:18]1[C@@H:35]2[CH2:36][C:23]3[CH:24]=[CH:25][C:26]([O:37][CH3:38])=[C:27]4[O:28][C@H:29]5[C:30]([CH2:32][CH2:33][C@@H:34]2[C@:21]5([C:22]=34)[CH2:20][CH2:19]1)=[O:31].Cl>O1CCOCC1>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:17][N:18]1[C@@H:35]2[CH2:36][C:23]3[CH:24]=[CH:25][C:26]([O:37][CH3:38])=[C:27]4[O:28][C@H:29]5[C:30]([CH2:32][CH2:33][C@@H:34]2[C@:21]5([C:22]=34)[CH2:20][CH2:19]1)=[O:31]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C[C@H](N)C(=O)O
Reaction time: 18 h

Procedure:
To the Boc-Leu-Hydrocodone was added 25ml of 4N HCl in dioxane. The resulting mixture was stirred at ambient temperatures for 18 hours. Solvent was removed and final product dried under vacuum. Solid was collected as a slightly yellow solid (1.96 g, 97% yield): 1H NMR (DMSO-d6) δ 0.94 (d, 6H), 1.52 (m, 1H), 1.75-1.90 (m, 4H), 2.22 (dt, 1H), 2.34 (dt, 1H), 2.64 (q, 1H), 2.75 (s, 3H), 2.95-3.23 (m, 4H), 3.74 (s, 3H), 3.91 (d, 1H), 4.07 (s, 1H), 5.10 (s, 1H), 5.72 (d, 1H), 6.76 (d, 1H), 6.86 (d, 1H), 8.73 br s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[C:4]([C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]1[S:16][C:11]2[CH2:12][O:13][CH:14]([CH3:15])[C:10]=2[C:9]=1[C:17]([OH:19])=O)=[O:6].Cl.[CH3:29][O:30][CH:31]1[CH2:34][NH:33][CH2:32]1>>[Cl:1][C:2]1[C:3]([F:27])=[C:4]([C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]1[S:16][C:11]2[CH2:12][O:13][CH:14]([CH3:15])[C:10]=2[C:9]=1[C:17]([N:33]1[CH2:34][CH:31]([O:30][CH3:29])[CH2:32]1)=[O:19])=[O:6]
Reactant: CC1OCc2sc(NC(=O)c3c(C(F)(F)F)ccc(Cl)c3F)c(C(=O)O)c21
Reactant: COC1CNC1
Agent: Cl
Product: COC1CN(C(=O)c2c(NC(=O)c3c(C(F)(F)F)ccc(Cl)c3F)sc3c2C(C)OC3)C1

Procedure:
The title compound was prepared from the product of Example 50A and commercially available 3-methoxyazetidine hydrochloride by the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.29 (d, J=6.4 Hz, 3H), 3.19 (s, 3H), 3.71-3.77 (m, 1H), 3.80-3.87 (m, 1H), 4.02-4.09 (m, 1H), 4.14-4.22 (m, 2H), 4.88-5.01 (m, 2H). 5.14-5.22 (m, 1H), 7.78 (d, J=9.1 Hz, 1H), 8.02 (dd, J=8.0, 8.0 Hz, 1H), 11.82 (br s, 1H). MS (ESI+) m/z 493 (M+H)+. Anal. calcd. for C20H17ClF4N2O4S: C, 48.74; H, 3.48; N, 5.68.